Methylmalonyl-CoA mutase deficiency
|Methylmalonyl-CoA mutase deficiency|
|Classification and external resources|
Methylmalonyl-CoA mutase is a mitochondrial homodimer apoenzyme (EC. 5. 4.99.2) that focuses on the catalysis of malonyl CoA to succinyl CoA. The enzyme is bound to adenosylcobalamin, a hormonal derivative of vitamin B12 in order to function. Methylmalonyl-CoA mutase deficiency, is caused by genetic defect in the MUT  gene responsible for encoding the enzyme. Deficiency in this enzyme accounts for 60% of the cases of methylmalonic acidemia.
Patients suffering from methylmalonyl CoA mutase deficiency exhibit many symptoms similar to other diseases involving inborn errors of metabolism. Neonates present with vomiting, acidosis, hyperammonemia, heptaomegaly, hypeglycinemia, and hypoglycemia. Later cases of thrombocytopenia and neutropenia can occur. Infants mortality is high for patients diagnosed with early onset; mortality can occur within less than 2 months, while children diagnosed with late-onset syndrome seem to have higher rates of survival  . Patients suffering from a complete lesion of mut0 have not only the poorest outcome of those suffering from methylaonyl-CoA mutase deficiency, but also of all individuals suffering from any form of methylmalonic acidemia. In some cases intellectual disabilities, such as autism, were noted with increased frequency in populations suffering from methylmalonyl-CoA mutase deficiency.
While methylmalonic acidemia has a variety of causes, both genetic and dietary, methylmalonyl CoA mutase deficiency is a autosomal recessive genetic disorder. Patients suffering from the deficiency either have a complete gene lesion, designated as mut0 or a partial mutation in the form of a frameshift designated as mut-. This frameshift affects the folding of the enzyme rendering its binding domain less effective. Patients with a complete deletion suffer an inactivation of methylmalonyl CoA mutase and exhibit the most sever symptoms of the deficiency, while patients with a partial mutations have a wide range of symptoms. Over 49 different mutations  have been discovered for the MUT gene, yet only two appear in any discernible frequency.
Effect on Metabolism
Methylmalonyl-CoA mutase is an important apoenzyme for the intramolecular transfer of a the ketone functional group on (R)-methylmalonyl-CoA in order to transform it into succynil-CoA . It is involved in numerous metabolic pathways, illustrated by Figure 1 and 2. Primarily, methylmalonyl-CoA mutase is involved in amino acid metabolism.
For amino acid metabolism, methylmalonyl-CoA mutase works in the degradation pathways of isoleucine, threonine, valine, and methionine. These amino acids are degraded into propanoyl-CoA which is then further degraded into (S)-methylmalonyl-CoA. This substrate must be further metabolized by a very similar enzyme, methylmalonyl-CoA epimerase, which converts the (S) form of methylmalonyl-CoA into the (R) form. This is finally transformed using methylmalonyl-CoA mutase. L-methionine is also metabolized through a longer superpathway (see Figure 2). After transformation to L-homocystein, it is combined with L-serine to make L-cystathione, which is hydrolyzed by cystathione gamma lyase to create 2-oxobutanoate. This substrate is transformed to propanoyl-CoA and undergoes the same metabolism previously described for propanoyl-CoA.
The final product of methylmalonyl-CoA mutase activity is succinyl-CoA which is a tricarboxylic acid cycle sybstrate. A side effect of excess methylmalonyl-CoA is an interruption of the enzymes responsible for other transformations earlier in the metabolism of proponyl-CoA, leading to propanoic acidemia as well. This, along with an excess of methylmalonyl-CoA leads to the the depletion of ATP through oxidative stress and coenzyme A. This disrupts the biosynthesis of myelin, urea, and glucose. Specifically, excess methylmalonyl-CoA places oxidative stress on the mitochondrial enzymes involved in the urea cycle (such as ammonia-dependent-carbamoyl-phosphate synthase), and inhibits its mechanism of action.
Diagnosis and Treatment
Several tests can be done to discover the dysfunction of methylmalonyl-CoA mutase. Ammonia test, blood count, CT scan, MRI scan, electrolyte levels, genetic testing, methylmalonic acid blood test, and blood plasma amino acid tests are all can all be conducted to determine deficiency.
There is no treatment for complete lesion of the mut0 gene, though several treatments can help those with slight genetic dysfunction. Liver and kydney tranplants, and a low protein diet all help regulate the effects of the diseases.
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- Online 'Mendelian Inheritance in Man' (OMIM) 251100
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